ENDOTHELIN-1 AND ENDOTHELIN-4 STIMULATE MONOCYTE PRODUCTION OF CYTOKINES

Objective: To determine the effect of endothelin-l and endothelin 4 on human monocyte production of cytokines. Design: Previous work from ou r laboratory has shown that endothelin-l activates leukocytes. Endothe lin-1 and endothelin-3 are principally produced by vascular endotheliu m. However, epidermal cells in gut mucosa, lung, and kidney produce en dothelin-2 and endothelin-4, which differ by a single amino acid. Whil e structurally similar to endothelin-1, endothelin-2 and endothelin-4 may affect gut smooth muscle and other tissues differently. The effect of endothelin-l and endothelin 4 was examined on monocyte production of interleukins (IL) and neutrophil activation factors. Setting: A cli nically-oriented basic science laboratory in a Veteran's Administratio n Hospital and Medical Center. Subjects: Healthy volunteer adult male/ female medical students, researchers, and hospital workers. Interventi ons: Human peripheral blood mononuclear cells were separated on densit y gradients and cultured in media, with or without the addition of bac terial endotoxin or varying molar concentrations of endothelin-1 and e ndothelin-4. Supernatants were harvested at 10 mins, and at 1, 6, 12, 24, and 48 hrs, and enzyme-linked immunosorbent assays were performed to determine the presence of tumor necrosis factor-alpha, IL-1 beta, I L-6, IL-8, and granulocyte-macrophage colony-stimulating factor. Concl usion: Endothelin-1 and endothelin-4 may activate leukocytes after sho ck or gut ischemia, resulting in further injury to reperfused tissues and distant injury to lungs and other organs.